8-azabicyclo[3.2.1]oct-2-ene derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

ABSTRACT

The present invention relates to novel 8-azabicyclo[3.2.1]oct-2-ene derivatives useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.

TECHNICAL FIELD

The present invention relates to novel 8-azabicyclo[3.2.1]oct-2-enederivatives useful as monoamine neurotransmitter re-uptake inhibitors.

In other aspects the invention relates to the use of these compounds ina method for therapy and to pharmaceutical compositions comprising thecompounds of the invention.

BACKGROUND ART

WO 02/30405 (NeuroSearch A/S) describes a group of8-azabicyclo[3.2.1]oct-2-ene derivatives having the dual activity of anicotinic reuptake inhibitor and a monoamine agonist or antagonist or amonoamine reuptake inhibitor. One of the compounds disclosed is theracemate (±)-3-(2-benzothienyl)-8H-8-azabicyclo[3.2.1]-oct-2-ene(compound 1D1, method D, page 16).

WO 2006/064031 (NeuroSearch A/S) describes the enantiomers of8-azabicyclo[3.2.1]oct-2-ene derivatives, such as(±)-3-(2-benzothienyl)-8H-8-azabicyclo[3.2.1]oct-2-ene, having apharmacological profile as monoamine reuptake inhibitors, in particularas regards the level of activity on reuptake of the monoamineneurotransmitters serotonin, dopamine and noradrenaline, such as theratio of the serotonin reuptake versus the noradrenaline and dopaminereuptake activity.

SUMMARY OF THE INVENTION

It is an object of the invention to provide novel compounds which showactivity as monoamine neurotransmitter re-uptake inhibitors.

In one aspect, the invention provides a compound of Formula (I):

any of its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof; wherein R¹ and R² are asdefined below.

In another aspect, the invention provides a pharmaceutical composition,comprising a therapeutically effective amount of a compound of theinvention, any of its enantiomers or any mixture of its enantiomers, ora pharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, excipient or diluent.

In another aspect, the invention provides the use of a compound of theinvention, any of its enantiomers or any mixture of its enantiomers, ora pharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment, prevention or alleviationof a disease or a disorder or a condition of a mammal, including ahuman, which disease, disorder or condition is responsive to inhibitionof monoamine neurotransmitter re-uptake in the central nervous system.

In another aspect, the invention relates to a method for treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disorder, disease orcondition is responsive to responsive to inhibition of monoamineneurotransmitter re-uptake in the central nervous system, which methodcomprises the step of administering to such a living animal body in needthereof a therapeutically effective amount of a compound of theinvention, any of its enantiomers or any mixture of its enantiomers, ora pharmaceutically acceptable salt thereof.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

In one aspect the present invention provides compounds of Formula (I):

any of its enantiomers or any mixture of its enantiomers or apharmaceutically acceptable salt thereof whereinR¹ represents hydrogen or C₁₋₆-alkyl; andR² represents hydroxy or C₁₋₆-alkoxy.

In one embodiment of the invention, in formula (I), R¹ representshydrogen. In another embodiment, R¹ represents C₁₋₆-alkyl, e.g. methyl,ethyl or propyl.

In another embodiment of the invention, in formula (I), R² representshydroxy. In another embodiment, R² represents C₁₋₆-alkoxy, e.g. methoxyor ethoxy.

In another embodiment of the invention, in formula (I), R¹ representshydrogen and R² represents hydroxy. In another embodiment, R¹ representshydrogen and R² represents methoxy. In another embodiment, R¹ representshydrogen and R² represents ethoxy.

In another embodiment of the invention, in formula (I), R¹ representsmethyl and R² represents hydroxy. In another embodiment, R¹ representsmethyl and R² represents methoxy. In another embodiment, R¹ representsmethyl and R² represents ethoxy.

In another embodiment of the invention, in formula (I), R¹ representshydrogen and R² represents 5-hydroxy. In another embodiment, R¹represents hydrogen and R² represents 5-methoxy.

In another embodiment of the invention, the compound of the inventionis:

-   (±)-3-(5-Methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene;-   (±)-2-(8-Aza-bicyclo[3.2.1]oct-2-en-3-yl)-benzo[b]thiophen-5-ol; or    a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a pharmaceutical composition,comprising a therapeutically effective amount of a compound of theinvention, any of its enantiomers or any mixture of its enantiomers, ora pharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, excipient or diluent.

In another aspect, the invention provides a pharmaceutical composition,comprising a therapeutically effective amount of the compound of formula(I), any of its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, wherein R¹ representshydrogen; and R² represents hydroxy or C₁₋₆-alkoxy, together with atleast one pharmaceutically acceptable carrier, excipient or diluent.

In another aspect, the invention provides a pharmaceutical composition,comprising a therapeutically effective amount of3-(5-methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene, anyof its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, excipient or diluent.

In another aspect, the invention provides a pharmaceutical composition,comprising a therapeutically effective amount of2-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-benzo[b]thiophen-5-ol, any of itsenantiomers or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof, together with at least one pharmaceuticallyacceptable carrier, excipient or diluent.

In another aspect, the invention provides a pharmaceutical composition,comprising a therapeutically effective amount of a compound of theinvention, any of its enantiomers or any mixture of its enantiomers, ora pharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, excipient or diluents, whichcomposition is for oral administration.

In another aspect, the invention provides a pharmaceutical composition,comprising a therapeutically effective amount of the compound of formula(I), any of its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, wherein R¹ represents hydrogenand R² represents hydroxy or C₁₋₆-alkoxy, of the invention, any of itsenantiomers or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof, together with at least one pharmaceuticallyacceptable carrier, excipient or diluents, which composition is for oraladministration.

In another aspect, the invention provides a pharmaceutical composition,comprising a therapeutically effective amount of3-(5-methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene, anyof its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, excipient or diluents, whichcomposition is for oral administration.

In another aspect, the invention provides a pharmaceutical composition,comprising a therapeutically effective amount of2-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-benzo[b]thiophen-5-ol, any of itsenantiomers or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof, together with at least one pharmaceuticallyacceptable carrier, excipient or diluents, which composition is for oraladministration.

In another aspect, the invention provides the use of a compound of theinvention, any of its enantiomers or any mixture of its enantiomers, ora pharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition.

In another aspect, the invention provides the use of the compound offormula (I), any of its enantiomers or any mixture of its enantiomers,or a pharmaceutically acceptable salt thereof, wherein R¹ representshydrogen and R² represents hydroxy or C₁₋₆-alkoxy, any of itsenantiomers or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a pharmaceuticalcomposition.

In another aspect, the invention provides the use of3-(5-methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene, anyof its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition.

In another aspect, the invention provides the use of2-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-benzo[b]thiophen-5-ol, any of itsenantiomers or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a pharmaceuticalcomposition.

In another aspect, the invention provides the use of a compound of theinvention, any of its enantiomers or any mixture of its enantiomers, ora pharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment, prevention or alleviationof a disease or a disorder or a condition of a mammal, including ahuman, which disease, disorder or condition is responsive to inhibitionof monoamine neurotransmitter re-uptake in the central nervous system.

In another aspect, the invention provides the use of the compound offormula (I), any of its enantiomers or any mixture of its enantiomers,or a pharmaceutically acceptable salt thereof, wherein R¹ representshydrogen and R² represents hydroxy or C₁₋₆-alkoxy, for the manufactureof a pharmaceutical composition for the treatment, prevention oralleviation of a disease or a disorder or a condition of a mammal,including a human, which disease, disorder or condition is responsive toinhibition of monoamine neurotransmitter re-uptake in the centralnervous system.

In another aspect, the invention provides the use of3-(5-methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene, anyof its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment, prevention or alleviationof a disease or a disorder or a condition of a mammal, including ahuman, which disease, disorder or condition is responsive to inhibitionof monoamine neurotransmitter re-uptake in the central nervous system.

In another aspect, the invention provides the use of2-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-benzo[b]thiophen-5-ol, any of itsenantiomers or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a pharmaceuticalcomposition for the treatment, prevention or alleviation of a disease ora disorder or a condition of a mammal, including a human, which disease,disorder or condition is responsive to inhibition of monoamineneurotransmitter re-uptake in the central nervous system.

In another aspect, the invention provides the use of a compound of theinvention, any of its enantiomers or any mixture of its enantiomers, ora pharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment, prevention or alleviationof a disease or a disorder or a condition which is mood disorder,depression, atypical depression, depression secondary to pain or majordepressive disorder.

In another aspect, the invention provides the use of the compound offormula (I), any of its enantiomers or any mixture of its enantiomers,or a pharmaceutically acceptable salt thereof, wherein R¹ representshydrogen and R² represents hydroxy or C₁₋₆-alkoxy, for the manufactureof a pharmaceutical composition for the treatment, prevention oralleviation of a disease or a disorder or a condition which is mooddisorder, depression, atypical depression, depression secondary to painor major depressive disorder.

In another aspect, the invention provides the use of3-(5-methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene, anyof its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment, prevention or alleviationof a disease or a disorder or a condition which is mood disorder,depression, atypical depression, depression secondary to pain or majordepressive disorder.

In another aspect, the invention provides the use of2-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-benzo[b]thiophen-5-ol, any of itsenantiomers or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a pharmaceuticalcomposition for the treatment, prevention or alleviation of a disease ora disorder or a condition which is mood disorder, depression, atypicaldepression, depression secondary to pain or major depressive disorder.

In another aspect, the invention provides the use of a compound of theinvention, any of its enantiomers or any mixture of its enantiomers, ora pharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment of depression.

In another aspect, the invention provides the use of the compound offormula (I), any of its enantiomers or any mixture of its enantiomers,or a pharmaceutically acceptable salt thereof, wherein R¹ representshydrogen and R² represents hydroxy or C₁₋₆-alkoxy, for the manufactureof a pharmaceutical composition for the treatment of depression.

In another aspect, the invention provides the use of3-(5-methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene, anyof its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment of depression.

In another aspect, the invention provides the use of2-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-benzo[b]thiophen-5-ol, any of itsenantiomers or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a pharmaceuticalcomposition for the treatment of depression

In another aspect, the invention relates to a method for treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disorder, disease orcondition is responsive to responsive to inhibition of monoamineneurotransmitter re-uptake in the central nervous system, which methodcomprises the step of administering to such a living animal body in needthereof a therapeutically effective amount of a compound of theinvention, any of its enantiomers or any mixture of its enantiomers, ora pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a method for treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disorder, disease orcondition is responsive to responsive to inhibition of monoamineneurotransmitter re-uptake in the central nervous system, which methodcomprises the step of administering to such a living animal body in needthereof a therapeutically effective amount of the compound of formula(I), any of its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, wherein R¹ represents hydrogenand R² represents hydroxy or C₁₋₆-alkoxy.

In another aspect, the invention relates to a method for treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disorder, disease orcondition is responsive to responsive to inhibition of monoamineneurotransmitter re-uptake in the central nervous system, which methodcomprises the step of administering to such a living animal body in needthereof a therapeutically effective amount of3-(5-methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene, anyof its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a method for treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disorder, disease orcondition is responsive to responsive to inhibition of monoamineneurotransmitter re-uptake in the central nervous system, which methodcomprises the step of administering to such a living animal body in needthereof a therapeutically effective amount of2-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-benzo[b]thiophen-5-ol, any of itsenantiomers or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof.

Any combination of two or more of the embodiments as described above isconsidered within the scope of the present invention.

Definition of Substituents

As used throughout the present specification and appended claims, thefollowing terms have the indicated meaning:

The term “C₁₋₆-alkyl” as used herein means a saturated, branched orstraight hydrocarbon group having from 1-6 carbon atoms, e.g.C₁₋₃-alkyl, C₁₋₄-alkyl, C₁₋₆-alkyl, C₂₋₆-alkyl, C₃₋₆-alkyl, and thelike. Representative examples are methyl, ethyl, propyl (e.g. prop-1-yl,prop-2-yl (or iso-propyl)), butyl (e.g. 2-methylprop-2-yl (ortert-butyl), but-1-yl, but-2-yl), pentyl (e.g. pent-1-yl, pent-2-yl,pent-3-yl), 2-methylbut-1-yl, 3-methylbut-1-yl, hexyl (e.g. hex-1-yl),and the like.

The term “hydroxy” shall mean the radical —OH.

The term “C₁₋₆-alkoxy” as used herein refers to the radicalC₁₋₆-alkyl-O—. Representative examples are methoxy, ethoxy, propoxy(e.g. 1-propoxy, 2-propoxy), butoxy (e.g. 1-butoxy, 2-butoxy,2-methyl-2-propoxy), pentoxy (1-pentoxy, 2-pentoxy), hexoxy (1-hexoxy,3-hexoxy), and the like.

Certain of the defined terms may occur more than once in the structuralformulae, and upon such occurrence each term shall be definedindependently of the other.

The term “treatment” as used herein means the management and care of apatient for the purpose of combating a disease, disorder or condition.The term is intended to include the delaying of the progression of thedisease, disorder or condition, the alleviation or relief of symptomsand complications, and/or the cure or elimination of the disease,disorder or condition. The patient to be treated is preferably a mammal,in particular a human being.

The terms “disease”, “condition” and “disorder” as used herein are usedinterchangeably to specify a state of a patient which is not the normalphysiological state of man.

The term “medicament” as used herein means a pharmaceutical compositionsuitable for administration of the pharmaceutically active compound to apatient.

The term “pharmaceutically acceptable” as used herein means suited fornormal pharmaceutical applications, i.e. giving rise to no adverseevents in patients etc.

The term “effective amount” as used herein means a dosage which issufficient in order for the treatment of the patient to be effectivecompared with no treatment.

The term “therapeutically effective amount” of a compound as used hereinmeans an amount sufficient to cure, alleviate or partially arrest theclinical manifestations of a given disease and its complications. Anamount adequate to accomplish this is defined as “therapeuticallyeffective amount”. Effective amounts for each purpose will depend on theseverity of the disease or injury as well as the weight and generalstate of the subject. It will be understood that determining anappropriate dosage may be achieved using routine experimentation, byconstructing a matrix of values and testing different points in thematrix, which is all within the ordinary skills of a trained physicianor veterinary.

Pharmaceutically Acceptable Salts

The compound of the invention may be provided in any form suitable forthe intended administration. Suitable forms include pharmaceutically(i.e. physiologically) acceptable salts, and pre- or prodrug forms ofthe compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride, the hydrobromide, the nitrate, the perchlorate,the phosphate, the sulphate, the formate, the acetate, the aconate, theascorbate, the benzenesulphonate, the benzoate, the cinnamate, thecitrate, the embonate, the enantate, the fumarate, the glutamate, theglycolate, the lactate, the maleate, the malonate, the mandelate, themethanesulphonate, the naphthalene-2-sulphonate, the phthalate, thesalicylate, the sorbate, the stearate, the succinate, the tartrate, thetoluene-p-sulphonate, and the like. Such salts may be formed byprocedures well known and described in the art.

Examples of pharmaceutically acceptable cationic salts of a compound ofthe invention include, without limitation, the sodium, the potassium,the calcium, the magnesium, the zinc, the aluminium, the lithium, thecholine, the lysinium, and the ammonium salt, and the like, of acompound of the invention containing an anionic group. Such cationicsalts may be formed by procedures well known and described in the art.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, thecycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

Examples of pre- or prodrug forms of the compound of the inventioninclude examples of suitable prodrugs of the substances according to theinvention include compounds modified at one or more reactive orderivatizable groups of the parent compound. Of particular interest arecompounds modified at a carboxyl group, a hydroxyl group, or an aminogroup. Examples of suitable derivatives are esters or amides.

The compound of the invention may be provided in dissoluble orindissoluble forms together with a pharmaceutically acceptable solventsuch as water, ethanol, and the like. Dissoluble forms may also includehydrated forms such as the monohydrate, the dihydrate, the hemihydrate,the trihydrate, the tetrahydrate, and the like. In general, thedissoluble forms are considered equivalent to indissoluble forms for thepurposes of this invention.

Steric Isomers

It will be appreciated by those skilled in the art that the compounds ofthe present invention may exist in different stereoisomericforms—including enantiomers, diastereomers or cis-trans-isomers.

The invention includes all such isomers and any mixtures thereofincluding racemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the enantiomeric compounds(including enantiomeric intermediates) is—in the case the compound beinga chiral acid—by use of an optically active amine, and liberating thediastereomeric, resolved salt by treatment with an acid. Another methodfor resolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of D- or L-(tartrates, mandelates,or camphorsulphonate) salts for example.

The compounds of the present invention may also be resolved by theformation of diastereomeric amides by reaction of the compounds of thepresent invention with an optically active activated carboxylic acidsuch as that derived from (+) or (−) phenylalanine, (+) or (−)phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the compound of the presentinvention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

Labelled Compounds

The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention the labelled compoundhas one or more atoms replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. The labelling will allow easy quantitative detection of saidcompound.

The labelled compounds of the invention may be useful as diagnostictools, radio tracers, or monitoring agents in various diagnosticmethods, and for in vivo receptor imaging.

The labelled isomer of the invention preferably contains at least oneradionuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this invention the radionuclideis preferably selected from ²H (deuterium), ³H (tritium), ¹¹C, ¹³C, ¹⁴C,¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F.

The physical method for detecting the labelled isomer of the presentinvention may be selected from Position Emission Tomography (PET),Single Photon Imaging Computed Tomography (SPECT), Magnetic ResonanceSpectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed AxialX-ray Tomography (CAT), or combinations thereof.

Methods of Preparation

The compounds of the invention may be prepared by conventional methodsfor chemical synthesis, e.g. those described in the working examples.The starting materials for the processes described in the presentapplication are known or may readily be prepared by conventional methodsfrom commercially available chemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Biological Activity

Compounds of the invention may be tested for their ability to inhibitreuptake of the monoamines dopamine, noradrenaline and serotonin insynaptosomes e.g. such as described in WO 97/30997 (NeuroSearch A/S).Based on the balanced activity observed in these tests the compound ofthe invention is considered useful for the treatment, prevention oralleviation of a disease or a disorder or a condition of a mammal,including a human, which disease, disorder or condition is responsive toinhibition of monoamine neurotransmitter re-uptake in the centralnervous system.

In one embodiment, the compounds of the invention are considered usefulfor the treatment, prevention or alleviation of: mood disorder,depression, atypical depression, depression secondary to pain, majordepressive disorder, dysthymic disorder, bipolar disorder, bipolar Idisorder, bipolar II disorder, cyclothymic disorder, mood disorder dueto a general medical condition, substance-induced mood disorder,pseudodementia, Ganser's syndrome, obsessive compulsive disorder, panicdisorder, panic disorder without agoraphobia, panic disorder withagoraphobia, agoraphobia without history of panic disorder, panicattack, memory deficits, memory loss, attention deficit hyperactivitydisorder, obesity, anxiety, generalized anxiety disorder, eatingdisorder, Parkinson's disease, parkinsonism, dementia, dementia ofageing, senile dementia, Alzheimer's disease, Down's syndrome, acquiredimmunodeficiency syndrome dementia complex, memory dysfunction inageing, specific phobia, social phobia, social anxiety disorder,post-traumatic stress disorder, acute stress disorder, drug addiction,drug abuse, drug abuse liability, cocaine abuse, nicotine abuse, tobaccoabuse, alcohol addiction, alcoholism, kleptomania, withdrawal symptomscaused by termination of use of addictive substances, pain, chronicpain, inflammatory pain, neuropathic pain, migraine pain, tension-typeheadache, chronic tension-type headache, pain associated withdepression, fibromyalgia, arthritis, osteoarthritis, rheumatoidarthritis, back pain, cancer pain, irritable bowel pain, irritable bowelsyndrome, post-operative pain, post-mastectomy pain syndrome (PMPS),post-stroke pain, drug-induced neuropathy, diabetic neuropathy,sympathetically-maintained pain, trigeminal neuralgia, dental pain,myofacial pain, phantom-limb pain, bulimia, premenstrual syndrome,premenstrual dysphoric disorder, late luteal phase syndrome,post-traumatic syndrome, chronic fatigue syndrome, persistent vegetativestate, urinary incontinence, stress incontinence, urge incontinence,nocturnal incontinence, sexual dysfunction, premature ejaculation,erectile difficulty, erectile dysfunction, premature female orgasm,restless leg syndrome, periodic limb movement disorder, eatingdisorders, anorexia nervosa, sleep disorders, pervasive developmentaldisorders, autism, Asperger's disorder, Rett's disorder, childhooddisintegrative disorder, learning disabilities, motor skills disorders,mutism, trichotillomania, narcolepsy, post-stroke depression,stroke-induced brain damage, stroke-induced neuronal damage, Gilles dela Tourettes disease, tinnitus, tic disorders, body dysmorphicdisorders, oppositional defiant disorder or post-stroke disabilities. Inanother embodiment, the compounds are considered useful for thetreatment, prevention or alleviation of depression.

It is at present contemplated that a suitable dosage of the activepharmaceutical ingredient (API) is within the range of from about 0.1 toabout 1000 mg API per day, more preferred of from about 10 to about 500mg API per day, most preferred of from about 30 to about 100 mg API perday, dependent, however, upon the exact mode of administration, the formin which it is administered, the indication considered, the subject andin particular the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

Preferred compounds of the invention show a biological activity in thesub-micromolar and micromolar range, i.e. of from below 1 to about 100μM.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thecompound of the invention.

While a compound of the invention for use in therapy may be administeredin the form of the raw chemical compound, it is preferred to introducethe active ingredient, optionally in the form of a physiologicallyacceptable salt, in a pharmaceutical composition together with one ormore adjuvants, excipients, carriers, buffers, diluents, and/or othercustomary pharmaceutical auxiliaries.

In one embodiment, the invention provides pharmaceutical compositionscomprising the compound of the invention, or a pharmaceuticallyacceptable salt or derivative thereof, together with one or morepharmaceutically acceptable carriers, and, optionally, other therapeuticand/or prophylactic ingredients, known and used in the art. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not harmful to therecipient thereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, pulmonal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The compound of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof. Such forms include solids, and inparticular tablets, filled capsules, powder and pellet forms, andliquids, in particular aqueous or non-aqueous solutions, suspensions,emulsions, elixirs, and capsules filled with the same, all for oral use,suppositories for rectal administration, and sterile injectablesolutions for parenteral use. Such pharmaceutical compositions and unitdosage forms thereof may comprise conventional ingredients inconventional proportions, with or without additional active compounds orprinciples, and such unit dosage forms may contain any suitableeffective amount of the active ingredient commensurate with the intendeddaily dosage range to be employed.

The compound of the present invention can be administered in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from a compound of the presentinvention, pharmaceutically acceptable carriers can be either solid orliquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier can be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets may contain from five or ten to about seventypercent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, a low melting wax, cocoa butter, and the like.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The compound according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, intended for conversionshortly before use to liquid form preparations for oral administration.Such liquid forms include solutions, suspensions, and emulsions. Inaddition to the active component such preparations may comprisecolorants, flavours, stabilisers, buffers, artificial and naturalsweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the compound of theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

In one embodiment, the invention provides tablets or capsules for oraladministration. In another embodiment, the invention provides tabletsfor oral administration. In another embodiment, the invention providescapsules for oral administration.

In another embodiment, the invention provides liquids for intravenousadministration and continuous infusion.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

A therapeutically effective dose refers to that amount of activeingredient, which ameliorates the symptoms or condition. Therapeuticefficacy and toxicity, e.g. ED₅₀ and LD₅₀, may be determined by standardpharmacological procedures in cell cultures or experimental animals. Thedose ratio between therapeutic and toxic effects is the therapeuticindex and may be expressed by the ratio LD₅₀/ED₅₀. Pharmaceuticalcompositions exhibiting large therapeutic indexes are preferred.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired, and the exact dosage should of course be determined by thepractitioner.

The actual dosage depends on the nature and severity of the diseasebeing treated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Ranges are from about 0.1 μg/kg to about 10 mg/kg/day i.v.,and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

In another aspect the invention provides a method for the treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disease, disorder orcondition is responsive to inhibition of monoamine neurotransmitterre-uptake in the central nervous system, and which method comprisesadministering to such a living animal body, including a human, in needthereof an effective amount of a compound of the invention.

It is at present contemplated that suitable dosage ranges are 0.1 to1000 milligrams daily, 10-500 milligrams daily, and especially 30-100milligrams daily, dependent as usual upon the exact mode ofadministration, form in which administered, the indication toward whichthe administration is directed, the subject involved and the body weightof the subject involved, and further the preference and experience ofthe physician or veterinarian in charge.

EXAMPLES

The following examples and general procedures refer to intermediatecompounds and final products for general formula (I) identified in thespecification. The preparation of the compounds of general formula (I)of the present invention is described in detail using the followingexamples. Occasionally, the reaction may not be applicable as describedto each compound included within the disclosed scope of the invention.The compounds for which this occurs will be readily recognized by thoseskilled in the art. In these cases the reactions can be successfullyperformed by conventional modifications known to those skilled in theart, which is, by appropriate protection of interfering groups, bychanging to other conventional reagents, or by routine modification ofreaction conditions. Alternatively, other reactions disclosed herein orotherwise conventional will be applicable to the preparation of thecorresponding compounds of the invention. In all preparative methods,all starting materials are known or may easily be prepared from knownstarting materials.

All reactions involving air sensitive reagents or intermediates areperformed under nitrogen and in anhydrous solvents. Magnesium sulphateis used as drying agent in the workup-procedures and solvents areevaporated under reduced pressure.

Example 13-(5-Methoxy-benzo[b]thiophen-2-yl)-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene(Intermediate Compound)

5-Methoxy-benzo[b]thiophene (3.20 g, 19.5 mmol) was solved indiethylether (50 ml). n-BuLi (8.58 ml, 21.45 mmol) was added to themixture at a temperature below 20° C. The cooling was removed and themixture was allowed to stir for 30 minutes. The mixture was cooled to−70° C. Tropinone (2.71 g, 19.5 mmol) solved in diethylether (50 ml) wasadded during 20 minutes. The temperature was kept below −60° C.Precipitation occurred. The mixture was stirred for 2 hours. Aqueoussodium hydroxide (20 ml, 1 M) was added. The mixture was stirred for 10minutes. The solid intermediate product(endo/exo-3-(5-methoxy-benzo-[b]thiophen-2-yl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol)was filtered and washed with water and diethylether. Yield 3.97 g (67%).The intermediate product was combined with acetic acid (20 ml) andhydrochloric acid (7 ml). The mixture was stirred at reflux for 1 hour.The mixture was poured out on ice. The mixture was made alkaline byadding ammonia and extracted with dichloromethane and washed with water.The crude mixture was purified by column chromatography using a mixtureof dichloromethane, methanol and aqueous ammonia (6:1:1%). Yield 2.28 g,(61%).

Example 23-(5-Methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-enehydrochloric acid salt (Compound 2.1)

3-(5-Methoxy-benzo[b]thiophen-2-yl)-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene(2.28 g, 7.99 mmol) was solved in toluene (25 ml).1-Chloroethylchloroformate (2.28 g, 15.97 mmol) was added atroom-temperature. The mixture was stirred at room-temperature for 1 hourand was then stirred at reflux for 15 hours. Methanol (20 ml) was addedfollowed by reflux for 2 hours. The mixture was cooled on an ice-bath.The product crystallized and was washed with ethanol and diethylether.The product was recrystallised from ethanol as hydrochloric acid salt,yield 0.37 g (15%). The mother liquor was evaporated, converted to thefree base by adding aqueous ammonia and extraction with dichloromethanefollowed by chromatographic purification using dichloromethane, methanoland aqueous ammonia (9:1+1%). Yield 0.30 g (14%).

LC-ESI-HRMS of [M+H]+shows 272.1098 Da. Calc. 272.11091 Da, dev. −4.1ppm.

Example 3 2-(8-Aza-bicyclo[3.2.1]oct-2-en-3-yl)-benzo[b]thiophen-5-olhydrochloric acid salt (Compound 3.1)

3-(5-Methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene (0.30g, 1.105 mmol) was solved in dichloromethane (25 ml) and was cooled onan ice-bath. Borontribromide (1 M, 2.21 ml, 2.21 mmol) was addeddropwise under cooling, followed by stirring for 15 hours atroom-temperature. Water (40 ml) was added and the mixture was madealkaline by adding aqueous ammonia. The product was filtered and wasrecrystallised with ethanol (25 ml, 96%) and HCl in ethanol (0.5 ml, 3M). Yield 0.15 g (46%).

LC-ESI-HRMS of [M+H]+ shows 258.0939 Da. Calc. 258.09526 Da, dev. −5.3ppm.

In Vitro Inhibition Activity

Compounds were tested for their ability to inhibit the reuptake of themonoamine neurotransmitters dopamine (DA) noradrenaline (NA) andserotonine (5-HT) in synaptosomes as described in WO 97/16451(NeuroSearch A/S).

The test values are given as IC₅₀ (the concentration (μM) of the testsubstance which inhibits the specific binding of ³H-DA, ³H-NA, or³H-5-HT by 50%).

Test results obtained by testing compounds of the present inventionappear from the below table:

TABLE 1 Test 5-HT-uptake DA-uptake NA-uptake compound IC₅₀ (μM) IC₅₀(μM) IC₅₀ (μM) 2.1 0.0025  0.74  0.057  3.1 0.00037 0.094 0.0043

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notto be limited as by the appended claims.

1. A compound of Formula I:

any of its enantiomers or any mixture of its enantiomers or apharmaceutically acceptable salt thereof wherein R¹ represents hydrogenor C₁₋₆-alkyl; and R² represents hydroxy or C₁₋₆-alkoxy.
 2. The compoundaccording to claim 1, any of its enantiomers or any mixture of itsenantiomers, or a pharmaceutically acceptable salt thereof, wherein R¹represents hydrogen.
 3. The compound according to claim 1, any of itsenantiomers or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof, wherein R² represents methoxy.
 4. The compoundaccording to claim 1, any of its enantiomers or any mixture of itsenantiomers, or a pharmaceutically acceptable salt thereof, wherein R²represents hydroxy.
 5. The compound according to claim 1, which is(±)3-(5-Methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene;(±)2-(8-Aza-bicyclo[3.2.1]oct-2-en-3-yl)-benzo[b]thiophen-5-ol; or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 1, any of its enantiomers or any mixture of its enantiomers, or apharmaceutically acceptable salt thereof, for use as a pharmaceuticalcomposition.
 7. The compound according to claim 1, any of itsenantiomers or any mixture of its enantiomers, or a pharmaceuticallyacceptable salt thereof, for use in the treatment or alleviation of adisease or a disorder or a condition of a mammal, including a human,which disease, disorder or condition is responsive to inhibition ofmonoamine neurotransmitter re-uptake in the central nervous system.
 8. Apharmaceutical composition, comprising a therapeutically effectiveamount of the compound of claim 1, any of its enantiomers or any mixtureof its enantiomers, or a pharmaceutically acceptable salt thereof,together with at least one pharmaceutically acceptable carrier,excipient or diluent.
 9. (canceled)
 10. (canceled)
 11. The methodaccording to claim 13, wherein the disease, disorder or condition ismood disorder, depression, atypical depression, depression secondary topain, major depressive disorder, dysthymic disorder, bipolar disorder,bipolar I disorder, bipolar II disorder, cyclothymic disorder, mooddisorder due to a general medical condition, substance-induced mooddisorder, pseudodementia, Ganser's syndrome, obsessive compulsivedisorder, panic disorder, panic disorder without agoraphobia, panicdisorder with agoraphobia, agoraphobia without history of panicdisorder, panic attack, memory deficits, memory loss, attention deficithyperactivity disorder, obesity, anxiety, generalized anxiety disorder,eating disorder, Parkinson's disease, parkinsonism, dementia, dementiaof ageing, senile dementia, Alzheimer's disease, Down's syndrome,acquired immunodeficiency syndrome dementia complex, memory dysfunctionin ageing, specific phobia, social phobia, social anxiety disorder,post-traumatic stress disorder, acute stress disorder, drug addiction,drug abuse, drug abuse liability, cocaine abuse, nicotine abuse, tobaccoabuse, alcohol addiction, alcoholism, kleptomania, withdrawal symptomscaused by termination of use of addictive substances, pain, chronicpain, inflammatory pain, neuropathic pain, migraine pain, tension-typeheadache, chronic tension-type headache, pain associated withdepression, fibromyalgia, arthritis, osteoarthritis, rheumatoidarthritis, back pain, cancer pain, irritable bowel pain, irritable bowelsyndrome, post-operative pain, post-mastectomy pain syndrome (PMPS),post-stroke pain, drug-induced neuropathy, diabetic neuropathy,sympathetically-maintained pain, trigeminal neuralgia, dental pain,myofacial pain, phantom-limb pain, bulimia, premenstrual syndrome,premenstrual dysphoric disorder, late luteal phase syndrome,post-traumatic syndrome, chronic fatigue syndrome, persistent vegetativestate, urinary incontinence, stress incontinence, urge incontinence,nocturnal incontinence, sexual dysfunction, premature ejaculation,erectile difficulty, erectile dysfunction, premature female orgasm,restless leg syndrome, periodic limb movement disorder, eatingdisorders, anorexia nervosa, sleep disorders, pervasive developmentaldisorders, autism, Asperger's disorder, Rett's disorder, childhooddisintegrative disorder, learning disabilities, motor skills disorders,mutism, trichotillomania, narcolepsy, post-stroke depression,stroke-induced brain damage, stroke-induced neuronal damage, Gilles dela Tourettes disease, tinnitus, tic disorders, body dysmorphicdisorders, oppositional defiant disorder or post-stroke disabilities.12. The method according to claim 13, wherein the disease, disorder orcondition is depression.
 13. A method for treatment or alleviation of adisease or a disorder or a condition of a living animal body, includinga human, which disorder, disease or condition is responsive toinhibition of monoamine neurotransmitter re-uptake in the centralnervous system, which method comprises the step of administering to sucha living animal body in need thereof a therapeutically effective amountof a compound according to claim 1, or any of its enantiomers or anymixture of its enantiomers, or a pharmaceutically acceptable saltthereof.